Pharmaceutical composition comprising a combination of metformin and a 4-oxobutanoic acid, and the use thereof for treating diabetes

ABSTRACT

The present invention relates to a pharmaceutical composition comprising, as active principles, metformin, optionally in the form of one of it its pharmaceutically acceptable salts, and a 4-oxobutanoic acid, in combination with one or more pharmaceutically acceptable excipients. These compositions are particularly suitable for treating non-insulin-dependent diabetes.

The present invention relates to a pharmaceutical compositioncomprising, as active principles, metformin, optionally in the form ofone of its pharmaceutically acceptable salts, and a 4-oxobutanoic acid.

The invention also relates to the use of metformin optionally in theform of one of its pharmaceutically acceptable salts and a 4-oxobutanoicacid, for the preparation of a medicinal preparation for reducinghyperglycaemia, more particularly the hyperglycaemia ofnon-insulin-dependent diabetes.

Diabetes is a chronic disease that has a number of pathologicalmanifestations. It is accompanied by disorders of lipid and sugarmetabolism and circulatory disorders. In many cases, diabetes tends toprogress to various pathological complications. Thus, it is necessary tofind a treatment that is suited to each individual suffering fromdiabetes.

Insulin resistance syndrome (syndrome X) is characterised by a reductionin the action of insulin (Presse Médicale, 26, No. 14, (1997), 671-677)and is involved in a great many pathological conditions, such asdiabetes and more particularly non-insulin-dependent diabetes,dyslipidaemia, obesity, arterial hypertension and also certainmicrovascular and macrovascular complications, for instanceatherosclerosis, retinopathies, nephropathies and neuropathies.

Metformin is mainly known for its anti-hyperglycaemiant activity and iswidely used in the treatment of non-insulin-dependent diabetes. Itimproves carbohydrate homeostasis by means of its peripheral action onmuscles and adipocytes by reducing the insulin resistance of diabeticpatients. Thus, in the case of non-insulin-dependent diabetes, metforminis also administered to the patient in combination with insulin, sincemetformin is known to improve the sensitivity to insulin. Metformin alsohas hepatic activity, by lowering neoglucogenesis and glycogenolysis [DeFronzo, Diabetes Reviews, 6 (1998), 89-131].

Insulin secretors that allow a reduction in hyperglycaemia in the caseof non-insulin-dependent diabetic patients correspond to anothertherapeutic category. These molecules bring about the secretion ofinsulin by acting on the pancreatic beta cells. They are first andforemost from the sulfonylurea family (such as gliclazide, glibenclamideand glymepiride). More recently, other types of molecules have appearedwith two novel insulin secretors. These are repaglinide (a benzoicderivative) and nateglinide (a phenylalanine derivative) [H. E.Lebovitz, Diabetes Reviews, 7 (1999), 139-152].

The sulfonylurea derivatives, repaglinide and nateglinide, cause closureof the ATP-dependent potassium channel in the pancreatic beta cells. Thesecretion of insulin is independent of the glucose concentration [A. S.Wagman; J. M. Nuss, Current Pharmaceutical Design, 7 (2001), 417-450].

Combinations of metformin with certain insulin secretors have alreadybeen described for treating diabetes, for instance the combinationmetformin-glyburide, a sulfonylurea described by Bristol Myers Squibb[WO 01/32157] and the combination of repaglinide or nateglinide with anantidiabetic compound including metformin has been described by Novartis[WO 01/21159].

4-Oxobutanoic acids have already been described for treating diabetes inpatent application WO 98/07681. Some of these compounds act on the earlyshort-lived secretion of insulin.

The specific combination of metformin optionally in the form of one ofits pharmaceutically acceptable salts with a 4-oxobutanoic acid has notbeen described, and offers particular advantages. In particular, thiscombination improves the diabetic patient's condition, especially byreducing the insulin resistance and affording increased control of theinsulin resistance in response to glucose.

Thus, one aim of the present invention is to propose a composition forsignificantly improving the diabetic patient's condition.

An aim of the invention is also to propose a composition that is suitedto the treatment of diabetes by means of a conjugate effect on insulinresistance syndrome and on the early short-lived secretion of insulin.

Finally, an aim of the invention is to propose a composition that isparticularly suitable for reducing hyperglycaemia and more particularlythe hyperglycaemia of non-insulin-dependent diabetes.

These aims and others are achieved by the present invention, whichrelates to a pharmaceutical composition comprising, as activeprinciples, metformin, optionally in the form of one of itspharmaceutically acceptable salts, and a compound of the formula (I), incombination with one or more pharmaceutically acceptable excipients.

This composition is particularly suitable for treating diabetes, moreparticularly non-insulin-dependent diabetes. It is particularly suitablefor reducing the hyperglycaemia of non-insulin-dependent diabetes.

It is also suitable for treating pathologies associated with insulinresistance syndrome, such as, especially, dyslipidaemia, obesity,arterial hypertension, and microvascular and macrovascularcomplications, for instance atherosclerosis, retinopathies,nephropathies and neuropathies.

The compound of the formula (I) is defined as follows:

in which the groups A and B are chosen, independently of each other,from:

-   -   a mono-, bi- or tricyclic aryl group containing from 6 to 14        carbon atoms;    -   a heteroaromatic group chosen from pyridyl, pyrimidyl, pyrrolyl,        furyl and thienyl groups;    -   an alkyl group containing from 1 to 14 carbon atoms;    -   a cycloalkyl group containing from 5 to 8 carbon atoms;    -   a saturated heterocyclic group chosen from tetrahydrofuryl,        tetrahydropyranyl, piperidyl and pyrrolidinyl groups;    -   the groups A and B possibly bearing 1 to 3 substituents chosen        from a C₁-C₆ alkyl group, a C₁-C6 alkoxy group, a C₆-C₁₄ aryl        group, a heteroaryl group chosen from pyridyl, pyrimidyl,        pyrrolyl, furyl and thienyl, a (C₆-C₁₄)aryl(C₁-C₆)-alkyl group,        a (C₆-C₁₄)aryl(C₁-C₆)alkyl(C₆-C₁₄)aryl group, a halogen or a        trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro,        amino, carboxyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,        (C₁-C₆)alkylsulfonyl, sulfoamino, (C₁-C₆)alkylsulfonylamino,        sulfamoyl or (C₁-C₆)alkylcarbonylamino group;    -   or two of the substituents forming a methylenedioxy group, a        solvate thereof or a salt of this acid.

In a preferred embodiment of the invention, the 4-oxobutanoic acids arethose of the formula (II) in which A and B are chosen from aryl groups.

Examples of aryl groups that may be mentioned include phenyl,α-naphthyl, β-naphthyl and fluorenyl groups.

The C₁-C₆ alkyl groups may be linear or branched. Examples that may bementioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl and pentyl groups.

The C₁-C₆ alkoxy groups may also be linear or branched.

Examples that may be mentioned include methoxy, ethoxy, propoxy,isopropoxy, butoxy and isobutoxy groups.

The halogens may be chosen from fluorine, chlorine, bromine and iodine.

The present invention also includes the tautomeric forms of thecompounds of the general formula (I), the enantiomers, diastereoisomersand epimers of these compounds, and also the solvates thereof.

Examples of salts of the compounds of the general formula (I) includepharmacologically acceptable salts, such as the sodium salts, potassiumsalts, magnesium salts, calcium salts, amine salts and other salts ofthe same type (aluminium, iron, bismuth, etc.).

In a preferred embodiment, the 4-oxobutanoic acids are chosen from:

-   -   2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid    -   2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid    -   2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic acid    -   2-benzyl-4-phenyl-4-oxobutanoic acid    -   2-(β-naphthylmethyl)-4-phenyl-4-oxobutanoic acid    -   2-benzyl-4-(β-naphthyl)-4-oxobutanoic acid    -   2-[(4-chlorophenyl)methyl]-4-(4-methoxyphenyl)-4-oxobutanoic        acid    -   2-benzyl-4-(4-methylphenyl)-4-oxobutanoic acid    -   4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-4-oxobutanoic        acid    -   2-benzyl-4-(3,4-methylenedioxyphenyl)-4-oxobutanoic acid    -   2-benzyl-4-cyclohexyl-4-oxobutanoic acid    -   4-phenyl-2-[(tetrahydrofur-2-yl)methyl]-4-oxobutanoic acid,        the solvates, enantiomers and salts of these acids.

The 4-oxobutanoic acid is advantageously chosen from:

-   -   (−)-2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid    -   (+)-2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid    -   (−)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid    -   (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

According to the invention, metformin or 1,1-dimethylbiguanide may beadministered in the form of one of its pharmaceutically acceptablesalts, such as the hydrochloride, acetate, benzoate, citrate, fumarate,embonate, chlorophenoxyacetate, glycolate, palmoate, aspartate,methanesulfonate, maleate, para-chlorophenoxyisobutyrate, formate,lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate,hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate,benzenesulfonate, trimethoxybenzoate, para-toluenesulfonate,adamantanecarboxylate, glyoxylate, glutamate, pyrrolidonecarboxylate,naphthalenesulfonate, glucose-1-phosphate, nitrate, sulfite, dithionate,phosphate, dobesilate, thioctate, hippurate, 3-benzamidopropanoate,glucuronate, L-pyrroli-done-5-carboxylate, cholate,α-glucose-1-phosphate, alginate or 4-aminobenzoate, and the salt withchondroitinsulfuric acid.

Among these salts, the hydrochloride, fumarate, embonate andchlorophenoxyacetate are more particularly preferred.

The pharmaceutically acceptable salts of metformin are obtained, in amanner that is known per se, by the action of metformin on thecorresponding acid.

The compositions of the invention comprise therapeutically effectiveamounts of the various active principles. The ratios of the respectiveamounts of metformin and of compound of the formula (I) thus vary inconsequence.

The weight ratio of metformin or of its pharmaceutically acceptable saltto the compound of the formula (I) preferably ranges from 1/1,preferably from 40/1 and better still from 2/1, to 20/1.

The compositions of the invention are preferably administeredparenterally or better still orally, although the otherroutes ofadministration, such as, for example, rectal administration, are notexcluded.

If oral administration is envisaged, the compositions of the inventionare in the form of gel capsules, effervescent tablets, coated oruncoated tablets, sachets, sugar-coated tablets, drinkable vials orsolutions, microgranules or sustained-release forms.

If parenteral administration is envisaged, the compositions of theinvention are in the form of injectable solutions and suspensionspackaged in vials or bottles for slow venous infusion.

The forms for oral administration are prepared by mixing the activesubstance with various types of excipients or of vehicles, such asfillers, disintegration (or crumbling) agents, binders, colorants,flavour enhancers and the like, followed by shaping of the mixture.

The colorant can be any colorant permitted for pharmaceutical use.

Examples of flavour enhancers include cocoa powder, mint, borneol andcinnamon powder.

Examples of binders that may be mentioned are polyvinylpyrrolidone,hydroxypropylmethylcellulose, alginic acid, carbomer,carboxymethylcellulose, dextrin, ethylcellulose, starch, sodiumalginate, polymethacrylate, maltodextrin, liquid glucose, magnesiumaluminium silicate, hydroxyethylcellulose, ethylcellulose,methylcellulose and guar gum.

It is possible to use alginic acid, sodium carboxymethylcellulose,colloidal silicon dioxide, sodium croscarmellose, crospovidone, guargum, magnesium aluminium silicate, methylcellulose, microcrystallinecellulose, potassium polacrilin, cellulose powder, pre-gelatinisedstarch, sodium alginate or sodium starch glycolate as disintegrationagent.

The fillers are, for example, cellulose, lactose, calcium hydrogenphosphate or microcrystalline cellulose.

The tablets can be obtained in a conventional manner by compressinggranules in the presence of one or more lubricants. Suitable lubricantsare calcium stearate, glyceryl monostearate, glyceryl palmitostearate,hydrogenated castor oil, hydrogenated plant oil, light mineral oil,magnesium stearate, polyethylene glycol, sodium benzoate, sodium laurylsulfate, stearyl sodium fumarate, stearic acid, talc and zinc stearate.These tablets can then be coated using polymers in solution orsuspension, such as hydroxypropylmethylcellulose or ethylcellulose.

The granules used to do this are prepared, for example, by using the wetgranulation process starting with a mixture of the active principleswith one or more excipients, such as a binder, a crumbling agent (ordisintegration agent) and a filler.

To obtain hard capsules, the mixture of active principles with asuitable filler (for example lactose) is incorporated into empty gelatincapsules optionally in the presence of a lubricant, such as magnesiumstearate, stearic acid, talc or zinc stearate.

Gel capsules or soft capsules are prepared by dissolving the activeprinciples in a suitable solvent (for example polyethylene glycol),followed by incorporation into soft capsules.

The forms for parenteral administration are obtained in a conventionalmanner by mixing the active principles with buffers, stabilisers,preserving agents, solubilising agents, tonicity agents and suspensionagents. In accordance with the known techniques, these mixtures aresubsequently sterilised and then packaged in the form of intravenousinjections.

As buffer, a person skilled in the art can use buffers based onorganophosphate salts.

Examples of suspension agents include methylcellulose,hydroxyethylcellulose, acacia and sodium carboxymethylcellulose.

Examples of solubilising agents include castor oil solidified withpolyoxyethylene, polysorbate 80, nicotinamide and macrogol.

In addition, stabilisers that are useful according to the invention aresodium sulfite and sodium metasulfite, while mention may be made ofsodium p-hydroxybenzoate, sorbic acid, cresol and chlorocresol aspreserving agents. For the preparation of an oral solution orsuspension, the active principles are dissolved or suspended in asuitable vehicle with a dispersant, a wetting agent, a suspension agent(for example polyvinylpyrrolidone), a preserving agent (such asmethylparaben or propylparaben), a flavour enhancer or a colorant.

For the preparation of suppositories, the active principles are mixed ina manner that is known per se with a suitable base constituent, such aspolyethylene glycol or semisynthetic glycerides.

For the preparation of microcapsules, the active principles are combinedwith suitable diluents, suitable stabilisers, agents that promote thesustained release of the active substances or any other type of additivefor the formation of a central core that is then coated with a suitablepolymer (for example a water-soluble resin or a water-insoluble resin).The techniques known to those skilled in the art will be used for thispurpose.

The microcapsules thus obtained are then optionally formulated insuitable dosage units.

The present invention also relates to the use of metformin, optionallyin the form of one of its pharmaceutically acceptable salts, incombination with a compound of the formula (I) as defined above for thepreparation of a medicinal combination for treating diabetes, moreparticularly non-insulin-dependent diabetes.

The present invention also relates to a process for treating diabetes,more particularly non-insulin-dependent diabetes, in a mammal,comprising the administration to the said mammal of the compositionaccording to the present invention.

The metformin may be in the form of any of the salts defined above;however, it is preferred to use metformin in unmodified form or in theform of the hydrochloride, fumarate, embonate or chlorophenoxyacetate.

If metformin or its salt and the compound of the formula (I) areincorporated into the same unit dose, the unit dose preferably comprisesfrom 50 to 1000 mg of metformin.

In this case, the unit dose advantageously comprises from 12.5 to 400 mgof compound of the formula (I).

Naturally, the dosage depends on the method of administration, thetherapeutic indication, and the age and condition of the patient.

In general, the daily dosage ranges between 100 and 2000 mg of metforminand between 12.5 and 400 mg of compound of the formula (I).

Specific but non-limiting examples of the invention will now bepresented.

EXAMPLE 1

A tablet having the composition below is prepared: mass in mg weight %Compound P 50 7.7 Metformin 500 76.7 Microcrystalline cellulose 40 6.1Fine lactose powder 30 4.6 Hydroxypropylcellulose 12 1.8 Sodiumcroscarmellose 12 1.8 Colloidal silica (Aerosil ®) 2 0.3 Magnesiumstearate 6 0.9Compound P: (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

EXAMPLE 2

A tablet having the composition below is prepared: mass in mg weight %Compound P 50 4.8 Metformin 850 81.1 Microcrystalline cellulose 50 4.8Fine lactose powder 45 4.3 Hydroxypropylcellulose 20 1.9 Sodiumcroscarmellose 20 3.1 Colloidal silica (Aerosil ®) 3 0.5 Magnesiumstearate 10 1.0Compound P: (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

EXAMPLE 3

A tablet having the composition below is prepared: mass in mg weight %Compound P 100 14.0 Metformin 500 69.9 Microcrystalline cellulose 40 5.6Fine lactose powder 36 5.0 Hydroxypropylcellulose 15 2.1 Sodiumcroscarmellose 15 2.3 Colloidal silica (Aerosil ®) 2 0.3 Magnesiumstearate 7 1.0Compound P: (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

EXAMPLE 4

A tablet having the composition below is prepared: mass in mg weight %Compound P 100 9.1 Metformin 850 77.4 Microcrystalline cellulose 50 4.6Fine lactose powder 44 4.0 Hydroxypropylcellulose 20 1.8 Sodiumcroscarmellose 21 3.2 Colloidal silica (Aerosil ®) 3 0.5 Magnesiumstearate 10 0.9Compound P: (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

EXAMPLE 5

A tablet having the composition below is prepared: mass in mg weight %Compound P 200 23.8 Metformin 500 59.6 Microcrystalline cellulose 50 6.0Fine lactose powder 42 5.0 Hydroxypropylcellulose 18 2.1 Sodiumcroscarmellose 20 3.1 Colloidal silica (Aerosil ®) 2 0.3 Magnesiumstearate 7 0.8Compound P: (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

EXAMPLE 6

A tablet having the composition below is prepared: mass in mg weight %Compound P 200 16.6 Metformin 850 70.4 Microcrystalline cellulose 50 4.1Fine lactose powder 45 3.7 Hydroxypropylcellulose 24 2.0 Sodiumcroscarmellose 25 3.8 Colloidal silica (Aerosil ®) 3 0.5 Magnesiumstearate 10 0.8Compound P: (+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.

1. Pharmaceutical composition comprising, as active principles, (i)metformin, optionally in the form of one of its pharmaceuticallyacceptable salts, and (ii) a compound of the formula (I), in combinationwith one or more pharmaceutically acceptable excipients, the compound ofthe formula (I) being defined as follows:

in which the groups A and B are chosen, independently of each other,from: a mono-, bi- or tricyclic aryl group containing from 6 to 14carbon atoms; a heteroaromatic group chosen from pyridyl, pyrimidyl,pyrrolyl, furyl and thienyl groups; an alkyl group containing from 1 to14 carbon atoms; a cycloalkyl group containing from 5 to 8 carbon atoms;a saturated heterocyclic group chosen from tetrahydrofuryl,tetrahydropyranyl, piperidyl and pyrrolidinyl groups; the groups A and Bpossibly bearing 1 to 3 substituents chosen from a C₁-C₆ alkyl group, aC₁-C₆ alkoxy group, a C₆-C₁₄ aryl group, a heteroaryl group chosen frompyridyl, pyrimidyl, pyrrolyl, furyl and thienyl, a(C₆-C₁₄)aryl(C₁-C₆)alkyl group, a (C₆-C₁₄)aryl(C₁-C₆)alkyl(C₆-C₁₄)arylgroup, a halogen or a trifluoromethyl, trifluoromethoxy, cyano,hydroxyl, nitro, amino, carboxyl, (C₁-C₆)alkoxycarbonyl, carbamoyl,(C₁-C₆)alkylsulfonyl, sulfoamino, (C₁-C₆)alkylsulfonylamino, sulfamoylor (C₁-C₆)alkylcarbonylamino group; or two of the substituents forming amethylenedioxy group, a solvate thereof or a salt of this acid. 2.Composition according to claim 1, characterised in that the4-oxobutanoic acid is of the formula (I) in which A and B are chosenfrom aryl groups.
 3. Composition according to claim 1, for treatingdiabetes.
 4. Composition according to claim 1, for treatingnon-insulin-dependent diabetes.
 5. Composition according to claim 1, fortreating at least one of the pathologies associated with insulinresistance syndrome, more particularly chosen from dyslipidaemia,obesity, arterial hypertension, and microvascular and macrovascularcomplications, for instance atherosclerosis, retinopathies,nephropathies and neuropathies.
 6. Pharmaceutical composition accordingto claim 1, characterised in that the weight ratio of metformin or ofits pharmaceutically acceptable salt to the compound of the formula (I)ranges from 1/1 to 40/1.
 7. Pharmaceutical composition according toclaim 1, characterised in that the metformin salt is a hydrochloride,fumarate, embonate or chlorophenoxyacetate.
 8. Composition according toclaim 1, characterised in that the compound of the formula (I) is chosenfrom: 2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic acid2-benzyl-4-phenyl-4-oxobutanoic acid2-(β-naphthylmethyl)-4-phenyl-4-oxobutanoic acid2-benzyl-4-(β-naphthyl)-4-oxobutanoic acid2-[(4-chlorophenyl)methyl]-4-(4-methoxyphenyl)-4-oxobutanoic acid2-benzyl-4-(4-methylphenyl)-4-oxobutanoic acid4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-4-oxobutanoic acid2-benzyl-4-(3,4-methylenedioxyphenyl)-4-oxobutanoic acid2-benzyl-4-cyclohexyl-4-oxobutanoic acid4-phenyl-2-[(tetrahydrofur-2-yl)methyl]-4-oxobutanoic acid, thesolvates, enantiomers and salts of these acids.
 9. Composition accordingto claim 8, characterised in that the compound of the formula (I) ischosen from: (−)-2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid(+)-2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid(−)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid(+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.
 10. Compositionaccording to claim 1, that is suitable for oral administration.
 11. Useof metformin, optionally in the form of one of its pharmaceuticallyacceptable salts, in combination with a compound of the formula (I) asdefined in claim 1 for the preparation of a medicinal combination fortreating diabetes.
 12. Use of metformin, optionally in the form of oneof its pharmaceutically acceptable salts, in combination with a compoundof the formula (I) as defined in claim 1 for the preparation of amedicinal combination for treating non-insulin-dependent diabetes. 13.Use of metformin, optionally in the form of one of its pharmaceuticallyacceptable salts, in combination with a compound of the formula (I) asdefined in claim 1 for the preparation of a medicinal combination fortreating at least one of the pathologies associated with insulinresistance syndrome, more particularly chosen from dyslipidaemia,obesity, arterial hypertension, and microvascular and macrovascularcomplications, for instance atherosclerosis, retinopathies,nephropathies and neuropathies.
 14. Use according to claim 11,characterised in that the metformin salt is a hydrochloride, a fumarate,an embonate or a chlorophenoxyacetate.
 15. Use according to claim 11,characterised in that the compound of the formula (I) is chosen from:2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid2-cyclohexylmethyl-4-(4-methoxyphenyl)-4-oxobutanoic acid2-benzyl-4-phenyl-4-oxobutanoic acid2-(β-naphthylmethyl)-4-phenyl-4-oxobutanoic acid2-benzyl-4-(β-naphthyl)-4-oxobutanoic acid2-[(4-chlorophenyl)methyl]-4-(4-methoxyphenyl)-4-oxobutanoic acid2-benzyl-4-(4-methylphenyl)-4-oxobutanoic acid4-(4-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-4-oxobutanoic acid2-benzyl-4-(3,4-methylenedioxyphenyl)-4-oxobutanoic acid2-benzyl-4-cyclohexyl-4-oxobutanoic acid 4-phenyl-2-[(tetrahydrofur-2-yl)methyl]-4-oxobutanoic acid, the solvates,enantiomers and salts of these acids.
 16. Use according to claim 11,characterised in that the compound of the formula (I) is chosen from:(−)-2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid(+)-2-benzyl-4-(4-methoxyphenyl)-4-oxobutanoic acid(−)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid(+)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid.
 17. Use according toclaim 11, characterised in that the medicinal combination is in the formof a unit dose comprising metformin or one of its pharmaceuticallyacceptable salts, and a compound of the formula (I).
 18. Use accordingto claim 17, characterised in that the unit dose comprises from 50 to1000 mg of metformin and from 12.5 to 400 mg of compound of the formula(I).